Submit to Special Issue Submit Abstract to Special Issue Review for IJMS Propose a Special Issue

Journal Menu

Journal Browser

Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: 20 May 2025 | Viewed by 7409

Share This Special Issue

Special Issue Editors

Dr. Judit Bene

E-Mail Website
Guest Editor

Department of Medical Genetics, Medical School, Clinical Center, University of Pécs, 7624 Pécs, Hungary
Interests: molecular genetics and genomics; next generation sequencing; rare diseases; genetic testing; neurocutaneous syndromes; copy number variations
Special Issues, Collections and Topics in MDPI journals

Dr. Kinga Hadzsiev

E-Mail Website
Guest Editor

Department of Medical Genetics, Medical School, University of Pécs, 7624 Pécs, Hungary
Interests: autism spectrum disorders; genomic disorders; epilepsy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Rare diseases, defined as life-threatening, chronically debilitating conditions, represent a substantial public health burden as they affect ca. 2–6% of the population. Currently, there are around 5000–8000 different rare diseases, and these numbers are continuing to increase. Despite intensive research, the genetic etiology and pathomechanisms of the majority of rare diseases are still unclear, and most of them do not yet have an approved therapy. Their diagnostics and care pathways are also challenging due to their rarity, heterogeneous manifestations, multisystem involvement and the often-observed incomplete penetrance. In addition, patients with undiagnosed genetic diseases often face a diagnostic odyssey that lasts for an average of eight years; moreover, a certain number of patients receive a misdiagnosis.

However, due to new sophisticated technologies, such as high-throughput sequencing and mass spectrometry, an increasing number of genomic and metabolomic data for various rare disorders have recently become available. These data could help us to understand biological mechanisms, identify new genes, determine causative mutations, discover biomarkers and ultimately develop novel therapeutics and diagnostics methods.

The aim of this Special Issue is to collect original and review articles that provide cutting-edge knowledge related to genetic, genomic and metabolomic investigations in rare disorders.

Dr. Judit Bene
Dr. Kinga Hadzsiev
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

rare diseases
genotype–phenotype analyses
NGS
mass spectrometry
biomarker discovery
molecular targeted therapy

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (8 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Other

20 pages, 3962 KiB

Open AccessArticle

Genetic Analysis of Choroideremia-Related Rab Escort Proteins

by Zhuo Xing, Fuguo Wu, Eduardo Cortes-Gomez, Annie Pao, Lingqiu Gao, Avrium Douglas, Yichen Li, Joseph A. Spernyak, G. William Wong, Prashant K. Singh, Jianmin Wang, Song Liu, Yasmin Thanavala, Ian M. MacDonald, Xiuqian Mu and Y. Eugene Yu

Int. J. Mol. Sci. 2025, 26(8), 3636; https://doi.org/10.3390/ijms26083636 - 11 Apr 2025

Viewed by 293

Abstract

Choroideremia is a rare X-linked recessive retinal disorder characterized by progressive vision loss caused by retinal degeneration resulting from mutations in the CHM gene, which encodes Rab escort protein 1 (REP-1). In humans and mice, the Rab escort protein (REP) family consists of two members, REP-1 and REP-2, with REP-2 hypothesized to compensate for REP-1 deficiency in tissues outside the eye in choroideremia. In this study, we conducted a systematic mutational analysis of the mouse orthologs of REP-1 and REP-2. Blood analyses revealed metabolic abnormalities in the mutant mice deficient for REP-1, resembling the systemic metabolic disturbances observed in individuals with choroideremia, such as altered lipid and hemoglobin metabolism. We also observed an elevation in systemic inflammatory biomarkers in these mutant mice. Interestingly, these systemic abnormalities emerged before retinal degeneration became detectable in REP-1-deficient mice. Transcriptomic analysis of retinas isolated from REP-1 deficient mice revealed enrichment of proinflammatory signaling pathways. These results suggest important similarities between choroideremia and some forms of retinitis pigmentosa. While engineered loss of REP-2 alone caused no detectable phenotypic changes, dual deficiency in REP-1 and REP-2 resulted in lethality under both in vivo and in vitro conditions. Our findings offer novel insights into REPs and deepen our understanding of choroideremia, which may contribute to the development of new treatments for this genetic condition. Full article

(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)

► Show Figures

Figure 1

14 pages, 9044 KiB

Open AccessArticle

Identification of POU1F1 Variants in Vietnamese Patients with Combined Pituitary Hormone Deficiency

by Ha Thu Nguyen, Khanh Ngoc Nguyen, Tran Minh Dien, Thi Bich Ngoc Can, Thi Thanh Ngan Nguyen, Nguyen Thi Kim Lien, Nguyen Van Tung, Nguyen Thi Xuan, Nguyen Thien Tao, Ngoc Lan Nguyen, Van Khanh Tran, Tran Thi Chi Mai, Van Anh Tran, Huy Hoang Nguyen and Chi Dung Vu

Int. J. Mol. Sci. 2025, 26(6), 2406; https://doi.org/10.3390/ijms26062406 - 7 Mar 2025

Viewed by 595

Abstract

Hypopituitarism is a condition characterized by the deficiency of several hormones produced by the pituitary gland. Genetic factors play an important role. Variants in the POU1F1 gene are associated with combined pituitary hormone deficiency 1 (CPHD1), which manifests as deficiencies in growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin (PRL). This study aimed to analyze the phenotype, genotype, treatment, and outcomes of Vietnamese patients with deficiency. Six patients from five unrelated families, initially diagnosed with hypopituitarism, were enrolled in this study. Data on physical characteristics, biochemical tests, treatment, outcomes, and follow-up were collected. Exome sequencing and Sanger sequencing were conducted to identify disease-causing variants in five probands and their families. All six patients exhibited anterior pituitary hypoplasia on brain magnetic resonance imaging and presented with TSH, GH, and PRL deficiencies. Exome sequencing identified three variants in the POU1F1 gene: c.428G>A p.(Arg143Gln), c.557T>G p.(Leu186Arg), and c.811C>T p.(Arg271Trp). The c.811C>T p.(Arg271Trp) variant was found in three patients, while c.557T>G p.(Leu186Arg) is a novel variant. Based on the ACMG classification, these variants were categorized as likely pathogenic or pathogenic variants. All patients were definitively diagnosed with CPHD1 caused by POU1F1 variants. All patients received levothyroxine and recombinant human growth hormone (rhGH) replacement therapy, leading to considerable growth. During the first year of treatment, all patients showed excellent growth response, with height increases ranging from 11 to 24 cm. After three years of treatment, two patients achieved normal height. One of the six patients developed scoliosis during treatment, which resolved after a one-year pause in rhGH therapy. Upon resuming treatment, no recurrence of scoliosis was observed. Our findings reveal the importance of early hormone testing and genetic analysis in improving the care and outcomes for patients with combined pituitary hormone deficiency. Full article

(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)

► Show Figures

Figure 1

11 pages, 1820 KiB

Open AccessArticle

Novel FANCI and RAD54B Variants and the Observed Clinical Outcomes in a Hungarian Melanoma Cohort

by Barbara Anna Bokor, Aliasgari Abdolreza, Flóra Kaptás, Margit Pál, Zita Battyani, Márta Széll and Nikoletta Nagy

Int. J. Mol. Sci. 2025, 26(1), 23; https://doi.org/10.3390/ijms26010023 - 24 Dec 2024

Viewed by 632

Abstract

Accumulating evidence suggests that inherited melanoma is not rare and approx. one in seven individuals with melanoma has clinically relevant hereditable cancer-predisposing and/or -susceptibility variant(s). Concerning its germline genetic background, genetic screening aims to identify either variants of predisposing genes with high penetrance or variants of susceptibility genes with medium or low penetrance. However, less attention is paid to genetic testing of germline variants of genes influencing patients’ survival outcomes or enhancing the design of new therapies. We aimed to investigate whether the germline genetic background of a Hungarian melanoma cohort (n = 17) contains any pathogenic or likely pathogenic variants of the BRCA2, POLE, WRN, FANCI, PALB2, and RAD54B genes and if the presence of these variants correlate with the clinical findings of the patients, including the advanced stage of melanoma, poor prognosis, and poor survival. We identified three novel variants in the FANCI gene and one novel variant in the RAD54B gene. We detected rapid disease progression, unfavorable outcome, and therapeutic resistance in the patient carrying the likely pathogenic FANCI variant. Our study highlights the importance of screening germline variants of genes influencing melanoma progression, therapy resistance, and survival of patients. Full article

(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)

► Show Figures

Figure 1

32 pages, 1265 KiB

Open AccessArticle

Concordance Between Biochemical and Molecular Diagnosis Obtained by WES in Mexican Patients with Inborn Errors of Intermediary Metabolism: Utility for Therapeutic Management

by Marcela Vela-Amieva, Miguel Angel Alcántara-Ortigoza, Ariadna González-del Angel, Liliana Fernández-Hernández, Miriam Erandi Reyna-Fabián, Bernardette Estandía-Ortega, Sara Guillén-López, Lizbeth López-Mejía, Leticia Belmont-Martínez, Rosa Itzel Carrillo-Nieto, Isabel Ibarra-González, Seung-Woo Ryu, Hane Lee and Cynthia Fernández-Lainez

Int. J. Mol. Sci. 2024, 25(21), 11722; https://doi.org/10.3390/ijms252111722 - 31 Oct 2024

Viewed by 1360

Abstract

Biochemical phenotyping has been the milestone for diagnosing and managing patients affected by inborn errors of intermediary metabolism (IEiM); however, identifying the genotype responsible for these monogenic disorders greatly contributes to achieving these goals. Herein, whole-exome sequencing (WES) was used to determine the genotypes of 95 unrelated Mexican pediatric patients suspected of having IEiM. They were classified into those bearing specific biochemical abnormalities (Group 1), and those presenting unspecific biochemical profiles (Group 2). The overall concordance between the initial biochemical diagnosis and final genotypic diagnoses was 72.6% (N = 69/95 patients), with the highest concordance achieved in Group 1 (91.3%, N = 63/69), whereas the concordance was limited in Group 2 (23.07%). This finding suggests that previous biochemical phenotyping correlated with the high WES diagnostic success. Concordance was high for urea cycle disorders (94.1%) and organic acid disorders (77.4%). The identified mutational spectrum comprised 83 IEiM-relevant variants (pathogenic, likely pathogenic, and variants of uncertain significance or VUS), including three novel ones, distributed among 29 different genes responsible for amino acid, organic acid, urea cycle, carbohydrate, and lipid disorders. Inconclusive WES results (7.3%, N = 7/95) relied on monoallelic pathogenic genotypes or those involving two VUS for autosomal-recessive IEiMs. A second monogenic disease was observed in 10.5% (N = 10/95) of the patients. According to the WES results, modifications in treatment had to be made in 33.6% (N = 32/95) of patients, mainly attributed to the presence of a second monogenic disease, or to an actionable trait. This study includes the largest cohort of Mexican patients to date with biochemically suspected IEiM who were genetically diagnosed through WES, underscoring its importance in medical management. Full article

(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)

► Show Figures

Figure 1

13 pages, 4911 KiB

Open AccessArticle

Molecular and Clinical Heterogeneity in Hungarian Patients with Treacher Collins Syndrome—Identification of Two Novel Mutations by Next-Generation Sequencing

by Gréta Antal, Anna Zsigmond, Ágnes Till, András Szabó, Anita Maász, Judit Bene and Kinga Hadzsiev

Int. J. Mol. Sci. 2024, 25(21), 11400; https://doi.org/10.3390/ijms252111400 - 23 Oct 2024

Viewed by 938

Abstract

Treacher Collins syndrome (TCS) is a rare congenital craniofacial disorder with variable penetrance and high genetic and phenotypic heterogeneity. It is caused by pathogenic variants in the TCOF1, POLR1D, POLR1C, and POLR1B genes, and its major characteristic features are malar and mandibular hypoplasia, downward slanting of the palpebral fissures, and conductive hearing loss. In this study, five patients (two males and three females, age range from 2 to 29 years) with TCS were tested by Next-Generation Sequencing (NGS)-based sequencing and clinically characterized. Genetic analyses detected two deletions and one insertion in the TCOF1 gene and one missense variant in the POLR1D gene. Two novel mutations, c.1371_1372insT (p.Lys458*) in the TCOF1 gene and c.295 G>C (p.Gly99Arg) in the POLR1D gene, were identified. Moreover, two already known mutations, c.4369_4373del (p.Lys1457Glufs*12) and c.2103_2106del (p.Ser701Argfs*9) in the TCOF1 gene, were detected. The novel TCOF1 c.1371_1372insT mutation was associated with mild craniofacial manifestations and very rare symptoms of TCS, i.e., developmental delay and moderate intellectual disability. Although incomplete penetrance is a known phenomenon in TCS, surprisingly, the majority of our patients inherited the disease-causing variants from an asymptomatic mother. The unique feature of our study is the observation of causative mutation transmission between asymptomatic family members. Our results expanded the clinical and mutational spectrum of TCS and further confirmed the inter- and intra-familial variability of this disorder. Full article

(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)

► Show Figures

Figure 1

12 pages, 5061 KiB

Open AccessCommunication

A De Novo Splicing Mutation of STXBP1 in Epileptic Encephalopathy Associated with Hypomyelinating Leukodystrophy

by Zixuan Wang, Jun Zhang, Yunfei Zhou, Guicen Liu, Zixin Tian and Xi Song

Int. J. Mol. Sci. 2024, 25(20), 10983; https://doi.org/10.3390/ijms252010983 - 12 Oct 2024

Viewed by 1253

Abstract

Deleterious variations in STXBP1 are responsible for early infantile epileptic encephalopathy type 4 (EIEE4, OMIM # 612164) because of its dysfunction in the central nervous system. The clinical spectrum of the neurodevelopmental delays associated with STXBP1 aberrations is collectively defined as STXBP1 encephalopathy (STXBP1-E), the conspicuous features of which are highlighted by early-onset epileptic seizures without structural brain anomalies. A girl was first diagnosed with unexplained disorders of movement and cognition, which later developed into STXBP1-E with unexpected leukoaraiosis and late onset of seizures. Genetic screening and molecular tests alongside neurological examinations were employed to investigate the genetic etiology and establish the diagnosis. A heterozygous mutation of c.37+2dupT at the STXBP1 splice site was identified as the pathogenic cause in the affected girl. The de novo mutation (DNM) did not result in any truncated proteins but immediately triggered mRNA degradation by nonsense-mediated mRNA decay (NMD), which led to the haploinsufficiency of STXBP1. The patient showed atypical phenotypes characterized by hypomyelinating leukodystrophy, and late onset of epileptic seizures, which had never previously been delineated in STXBP1-E. These findings strongly indicated that the haploinsufficiency of STXBP1 could also exhibit divergent clinical phenotypes because of the genetic heterogeneity in the subset of encephalopathies. Full article

(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)

► Show Figures

Figure 1

Other

Jump to: Research

13 pages, 4083 KiB

Open AccessCase Report

A Novel Pathogenic Variant of DICER1 Gene in a Young Greek Patient with 2 Different Sex-Cord Ovarian Tumors and Multinodular Goiter

by Afroditi Roumpou, Argyro-Ioanna Ieronimaki, Aspasia Manta, Ioannis G. Panayiotides, Constantine A. Stratakis, Sophia Kalantaridou and Melpomeni Peppa

Int. J. Mol. Sci. 2025, 26(5), 1990; https://doi.org/10.3390/ijms26051990 - 25 Feb 2025

Viewed by 522

Abstract

DICER1 syndrome (DICERs) represents a tumor predisposition genetic syndrome, inherited in an autosomal dominant manner. Germline loss-of-function variants of the DICER1 gene lead to impaired processing of microRNA, gene expression, and increased risk of tumorigenesis. Although pleuropulmonary blastoma (PPB) is the hallmark of the syndrome, multiple extrapulmonary malignant and non-malignant conditions have also been described, including multinodular goiter (MNG) and sex-cord stromal tumors. MNG is one of the most common components and is associated with an increased risk of thyroid carcinoma. Sertoli–Leydig cell tumor (SLCT) represents the most prevalent type of sex-cord stromal tumor associated with the syndrome, whereas juvenile granulosa cell tumor (JGCT) is considered to be a very rare phenotype. They both may present with abdominal pain due to mass effect and menstrual irregularities in case of hormone production. Although they exhibit low rates of mortality, recurrence rates highly depend on the grade of malignancy. Herein, we report a novel pathogenic DICER1 variant associated with MNG, bilateral ovarian SLCT, and JGCT in a young Greek patient. Clinicians should be aware of a potential germline DICER1 variant when evaluating MNG in young patients, especially if it coexists with other neoplasms. Full article

(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)

► Show Figures

Figure 1

9 pages, 1873 KiB

Open AccessBrief Report

Cell-Penetrating Peptide Enhances Tafazzin Gene Therapy in Mouse Model of Barth Syndrome

by Rahul Raghav, Junya Awata, Gregory L. Martin, Douglas Strathdee, Robert M. Blanton and Michael T. Chin

Int. J. Mol. Sci. 2024, 25(24), 13560; https://doi.org/10.3390/ijms252413560 - 18 Dec 2024

Viewed by 1041

Abstract

Barth Syndrome (BTHS) is an early onset, lethal X-linked disorder caused by a mutation in tafazzin (TAFAZZIN), a mitochondrial acyltransferase that remodels monolysocardiolipin (MLCL) to mature cardiolipin (CL) and is essential for normal mitochondrial, cardiac, and skeletal muscle function. Current gene therapies in preclinical development require high levels of transduction. We tested whether TAFAZZIN gene therapy could be enhanced with the addition of a cell-penetrating peptide, penetratin (Antp). We found that TAFAZZIN-Antp was more effective than TAFAZZIN at preventing the development of pathological cardiac hypertrophy and heart failure. These findings indicate that a cell-penetrating peptide enhances gene therapy for BTHS. Full article

(This article belongs to the Special Issue Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances)

► Show Figures

Journal Menu

Journal Browser

Exploring Rare Diseases: Genetic, Genomic and Metabolomic Advances

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (8 papers)

Research

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI